The present invention comprises a chemically efficient one step process for the synthesis of intermediates useful in the synthesis of antifungal agents.
PCT International Publication No. WO 89/04829, U.S. Pat. No. 5,039,676, and PCT International Publication No. WO 93/09114 disclose substituted tetrahydrofuran azole compounds having utility as antifungal agents. A number of processes for the synthesis of these compounds are known. In particular, co-owned, co-pending U.S. Ser. No. 08/055,268 describes a process for preparing chiral intermediates for use in the preparation of these antifungal agents. Dialkyl malonate derivatives of the formula I ##STR2## wherein R is C.sub.1 -C.sub.6 alkyl, are important intermediates used in this process. An efficient synthesis of compounds of the formula I is therefore a key factor in the synthesis of antifungal compounds via this process.
U.S. Ser. No. 08/055,268 discloses a process for preparing compounds of the formula I. This process, as shown in Reaction 1 ,comprises reacting a dialkyl malonate anion, wherein M.sup.+ is a suitable metal counterion and R is C.sub.1 -C.sub.6 alkyl, with a compound of the formula II, wherein Z is a leaving group selected from Br, --OSO.sub.2 CH.sub.3 or --OSO.sub.2 C.sub.6 H.sub.4 CH.sub.3, to form a compound of formula I. However, the process is inefficient in that a multistep process is necessary to prepare the starting compounds of formula lI. ##STR3##
The carbopalladation of allenes is disclosed by Ahmar, et al in Tetrahedron, 43(3), 513-526 (1987) and Ahmar, et al in Tet. Lett., 25 (40), 4505-4508 (1984). The Ahmar et al publications disclose carbopalladation reactions involving iodobenzene, allene and sodio diethyl malonate to form a compound of the formula IV ##STR4## The Ahmar et al publications also teach such reactions using bromobenzene and 1,2-decadiene.